NO328132B1 - Chromium derivatives, processes for their preparation, use of the compounds as intermediates for the synthesis of drugs, and processes for the preparation of a particular chromane derivative and its salts. - Google Patents

Description

The invention relates to chromane derivatives of formula I

where

R<1> means acyl with 1-6 C atoms, -CO-R<5>, phenylacetyl, phenoxyacetyl, methoxyacetyl, ethoxyacetyl, 2,2,2-trichloroethoxycarbonyl, tert.-butoxycarbonyl, 2-iodoethoxycarbonyl, carbobenzoxoxycarbonyl, 4 -methoxybenzyloxycarbonyl, 9-fluorenymethoxycarbonyl or 4-methoxy-2,3,6-trimethylphenylsulfonyl,

R<2> means H or alkyl with 1-6 C atoms,

R<3>, R<4> independently means H, alkyl with 1-6 C atoms, CN, Hal or COOR<2>, R means unsubstituted or once or twice with alkyl with 1-6 C atoms , OR or

Hal substituted phenyl,

X means H, H or O, and

Hal means F, Cl, Br or I,

as well as their salts,

with N-(chroman-2-ylmethyl)-cyclopropanecarboxylic acid amide being excluded.

The object of the invention is also the optically active forms, the racemates, the enantiomers as well as the hydrates and solvates, for example the alcoholates, of these compounds.

Similar compounds are known from EP 0 707 007.

From US 5,318,988 similar chromane derivatives are known, prepared either by alkylation, reductive amidation or reductive alkylation, such as for example N-(chroman-2-ylmethyl)-cyclopropanecarboxylic acid amide.

The invention was based on the task of finding new compounds that can be used in particular as intermediates in the synthesis of pharmaceuticals.

It was found that the compounds of formula I and their salts constitute important intermediates for the production of pharmaceuticals, particularly of those which, for example, have effects on the central nervous system.

The object of the invention is the chromane derivatives of formula I and their salts.

Above and below, the residues R<1>, R<2>, R<3>, R4, R5 and X have the meanings given for the formulas I-II unless otherwise expressly stated.

In the formulas above, alkyl has 1-6, preferably 1, 2, 3 or 4 C atoms. Alkyl preferably means methyl or ethyl, also propyl, isopropyl, further also butyl, isobutyl, sec.-butyl or tert.-butyl. Acyl has 1-6, preferably 1,2, 3 or 4 carbon atoms. Acyl means in particular acetyl, propionyl or butyryl.

R<2> preferably means H, further also methyl, ethyl or propyl.

R<3> and R<4> preferably mean H.

R<5> preferably means, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl.

The residue R<1> means acyl, -CO-R<5> or also one of the per se known amino protecting groups indicated above.

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are however easily removable after the desired chemical reaction has been carried out elsewhere in the molecule . As the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size are otherwise not of decisive importance. Preferred amino protecting groups are BOC (tert.-butoxy-carbonyl) and Mtr (4-methoxy-2,3,6-trimethylphenylsulfonyl), further CBZ (carbobenzoxycarbonyl, also called "Z") or FMOC (9-fluorenylmethoxycarbonyl).

The compounds of formula I can have one or more chiral centers and thus occur in different stereoisomeric forms. Formula I includes all these forms.

The object of the invention is further a method for the production of chromane derivatives of formula I according to claim 1, as well as of their salts, where X means O, characterized in that a compound of formula II

where R 1 , R *} , R " X , R A have the meanings specified in claim 1 and X means O,

is hydrogenated using an enantiomer-enriching catalyst.

The object of the invention is also a method for the production of chromane derivatives of formula I according to claim 1, as well as of their salts, where X means H,H, characterized in that a compound of formula II where R<1>, R2, R<3>, R<4> has the meanings given in claim 1, and X means O, is hydrogenated with the aid of an enantiomer-enriching catalyst, and then reduced in the usual way.

In particular, it was found that (2-acetylaminomethyl)-chroman-4-one can be hydrogenated with various enantiomerically pure rhodium-diphosphane complexes to enantiomerically enriched (2-acetylaminomethyl)-chroman-4-one.

The object of the invention is also a method for the production of chromane derivatives of formula I, characterized in that the enantiomer-enriching catalyst is a transition metal complex.

Particularly preferably, the catalyst is a transition metal complex containing a metal selected from the group rhodium, iridium, ruthenium and palladium.

The object of the invention is further a method for the production of chromane derivatives of formula I, characterized in that the catalyst is a transition metal complex where the transition metal is complexed with a chiral diphosphane ligand.

The following ligands should be mentioned as examples:

Depending on the choice of (R)- or (S)-enantiomers of the ligands in the catalyst, the (R)- or (S)-enantiomer is obtained in excess.

Compounds such as Rh(COD)2-OTf (rhodium cyclooctadiene triflate, [Rh(COD)Cl]2, Rh(COD)2BF4, [Ir(COD)Cl]2, Ir(COD) serve as precursors for the chiral ligands 2BF4 or [Ru(COD)Cl2]x.

The compounds of formula I and also the starting compounds for their production are otherwise prepared according to procedures known per se, as they have been described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der Organischen Chemie, Georg-Thieme-Verlag, Stuttgart), and then under reaction conditions that are known and suitable for the aforementioned conversions. In this way, you can also make use of variants that are known in and of themselves, and are not explained in more detail here.

If desired, the starting compounds can also be formed in situ so that they are not isolated from the reaction mixture, but are immediately converted further into the compounds of formula I.

The compounds of formula II are partially known; the unknown compounds can easily be prepared analogously to the known compounds. The conversion of a compound of formula II where X means O to a compound of formula I where X means O takes place according to the present invention by hydrogen gas with the aid of an enantiomer-enriching catalyst in an inert solvent such as methanol or ethanol.

Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene are also suitable as inert solvents; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglym); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; optionally also mixtures of the mentioned solvents with each other or mixtures with water.

Depending on the conditions used, the reaction time for the enantioselective hydrogenation is between a few minutes and 14 days, the reaction temperature between 0 and 150 °C, normally between 20 and 130 °C. In the usual way, the catalyst/substrate ratio is between 1:2000 and 1:50, particularly preferably at 1:1000 to 1:100. The reaction time is then, for example, between 3 and 20 hours. The hydrogenation is carried out under 1-200 bar hydrogen, preferably at 3-100 bar.

The conversion of a compound of formula II where X means O to a compound of formula I where X means H,H takes place according to the invention with hydrogen gas by means of an enantiomer-enriching catalyst in an inert solvent such as methanol or ethanol, as described above, followed by of a conversion of the 4-oxo group into a methylene group under known conditions. The reduction preferably takes place with hydrogen gas under transition metal catalysis (e.g. by hydrogenation on Raney nickel or Pd-carbon in an inert solvent such as methanol or ethanol).

The conversion of compounds of formula I where R<3>, R4 means COOalkyl, to compounds of formula I where R<3>,R<4> means COOH, takes place, for example, with NaOH or KOH in water, water-THF or water- dioxane at temperatures between 0 and 100 °C.

The cleavage of a residue R<1> from a compound of formula I takes place, depending on the protecting group used, e.g. with strong acids, suitably with TFA (trifluoroacetic acid) or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid, or sulphonic acids such as benzene or p-toluenesulphonic acid. The presence of an additional inert solvent is possible, but not necessary. Suitable inert solvents are preferably organic, e.g. carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide, halogenated carbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, as well as water. Furthermore, there are mixtures of the above-mentioned solvents. TFA is preferably used in excess without the addition of further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures are conveniently between about 0 and about 50 °C, preferably working between 15 and 30 °C.

The group BOC is preferably cleaved with TFA in dichloromethane or with approx. 3 to 5 N hydrochloric acid in dioxane at 15-30 °C. The removal of the acetyl group takes place according to usual methods (PJ. Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994).

Hydrogenolytically removable protecting groups (e.g. CBZ or benzyl) can

e.g. split off by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, suitably on a carrier such as carbon). Suitable solvents are those indicated above, particularly alcohols such as methanol or ethanol, or amides such as DMF. The hydrogenolysis is usually carried out at temperatures between about 0 and 100 °C, and pressure between about 1 and 200 bar, preferably at 20-30 °C and 1-10 bar. A base of formula I can be transferred with an acid to the corresponding acid addition salt, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol, and with subsequent evaporation. For this turnover, acids that give physiologically acceptable salts are particularly relevant. Thus, inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, precursor acids such as orthophosphoric acid, sulfamic acid, further organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulphonic or sulfuric acids , e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and -disulfonic acids, and laurylsulphuric acid. Add salt

physiologically unacceptable acids, e.g. picrates, can be used for isolation and/or purification of the compounds of formula I.

On the other hand, compounds of formula I can be converted with bases (eg sodium or potassium hydroxide or carbonate) in the corresponding metal, especially alkali metal or alkaline earth metal salts, or in the corresponding ammonium salts.

The object of the invention is also the use of the compounds of formula I as intermediates for the synthesis of pharmaceuticals. Corresponding medicines are described, for example, in EP 0 707 007.

The object of the invention is thus particularly the use of the compounds of formula I according to claim 1 in the synthesis of

(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman and its salts, characterized in that one

a) hydrogenates a compound of formula II

where

R<1> has the meaning specified in claim 1,

R<2>, R3 and R<4> mean H and X means 0,

with the help of an enantiomer-enriching catalyst,

b) that from the thus obtained enantiomerically enriched mixture of (R) and (S) compounds of formula I, where R1 has the meaning stated in claim 1,

R<2>, R<3> and R<4> mean H, and X means O,

recovers the enantiomeric (R) compound of formula I, wherein

R<1> has the meaning specified in claim 1,

R<2>, R<3> and R<4> mean H and X means O,

by crystallization,

c) that the enantiomeric (R) compound of formula I is then reduced in the usual way, where

R<1> has the meaning specified in claim 1,

R<2>, R3 and R<4> mean H and X means O,

d) that from the thus obtained (R) compound of formula I, where

R has it in claim. 1 stated meaning,

R<2>, R<3> and R<4> mean H and X means H,H,

split off the remainder R<1>,

e) that one converts the (R)-(chroman-2-ylmethyl)-amine thus obtained into an acid addition salt and converts this in a known manner to (R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl] -chromane, and optionally converts this into its acid addition salt,

the recovery of the (R)-enantiomer can be carried out by crystallization from the enantiomer-enriched (R,S) mixture also after step c) or after step d).

The object of the invention is further the use of the compounds of formula I as intermediates for the synthesis of drugs which have effects on the central nervous system.

Above and below, all temperatures are given in °C. In the following examples, "usual work-up" means: if necessary, water is added, if necessary, adjusted, depending on the constitution of the final product, to a pH value between 2 and 10, it is extracted with ethyl acetate or dichloromethane, separated, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and/or by crystallization. Rf value on silica gel.

EXAMPLES

Experimental data (complex preparation, hydrogenation, analysis):

All reactions were carried out under inert conditions (i.e. water-free and oxygen-free reaction conditions).

1. Preparation of the catalyst-substrate solution:

1.1 Example:

11.2 mg of Rh(COD) 2 OTf (rhodium cyclooctadiene triflate) was dissolved in 5 ml of methanol and it was cooled to 0 °C. Then a cooled solution of 1.1 equiv. bisphosphane (e.g. 12.6 mg (R, R)-Skewphos) in 5 ml methanol added. After stirring for 10 minutes at room temperature, the complex solution was added with the substrate solution consisting of 110 mg of (2-acetylaminomethyl)-chromen-4-one in 10 ml of methanol.

1.2 Example:

51.4 mg of [Rh(COD)Cl]2 was dissolved in 4 ml of the solvent mixture toluene/methanol in the ratio 5:1, and a solution consisting of 5 ml of toluene, 1 ml of methanol and 1.1 equiv was added. bisphosphane (e.g. 130.6 mg (R)-BINAP). To 1 ml of this catalyst complex solution was added 510.8 mg of (2-acetylaminomethyl)-chromen-4-one dissolved in 15 ml of toluene and 3 ml of methanol.

2. Enantioselective hydrogenation

The catalyst-substrate solution to be hydrogenated was filled in an autoclave in protective gas countercurrent. The protective gas atmosphere was replaced by several blow-throughs with hydrogen (1-5 bar H2 atmosphere). The mixture analogous to 1.1 reacted immediately at room temperature and 5 bar hydrogen. The catalyst analogous to 1.2 gave the best result at 50 °C and 80 bar hydrogen. As a rule, the hydrogenation was interrupted after 15 hours.

3. Probe name and analytics

A probe was taken up in the shielding gas counterflow. The complex was separated for determination of the enantiomeric excess by column chromatography on silica gel (eluent: ethyl acetate). The enantiomeric excess of the hydrogenation product was determined on chiral HPLC phase: Column: Daicel Chiracel OJ (Inner diameter x length/mm: 4.6 x 250) Eluent: n-hexane: i-propanol = 9:1

Flow rate: 0.8 ml/min (18 bar, 28 °C)

Detection: UV: 250 nm

Retention: Rt ( R) = 27 min.; Rt (5) = 29 min.

The evaporation of the impure hydrogenation solution led to precipitation of the product. An elevation of the enantiomeric excess was determined by means of the fractional crystallization.

4. Further reduction

After a complete conversion was determined, reduction of the keto group using palladium-carbon followed as a one-step procedure. To the crude ketone solution resulting from the homogeneous hydrogenation, 10% by weight of water-moistened palladium-carbon (eg 100 mg of water-moistened Pd/C to 1 g of (2-acetylaminomethyl)-chromen-4-one) and 1 ml of glacial acetic acid were added. At 7 bar hydrogen pressure and 50 °C the hydrogens are kept for 14 hours.

5. Processing and analytics

The palladium carbon was removed by filtration. The enantiomeric excess of the hydrogenation product was determined on chiral HPLC phase: Column: Daicel Chiracel OJ (Inner diameter x length/mm: 4.6 x 250) Eluent: n-hexane: i-propanol = 9:1

Flow rate: 0.8 ml/min (18 bar, 28 °C)

Detection: UV: 250 nm

Retention: Rt ( R) = 25 min.; Rt (S) = 27 min.

During the reduction with palladium-carbon, the enantiomeric excess remained unchanged. The evaporation of the impure hydrogenation solution led to precipitation of the product. An increase of the enantiomeric excess was determined by means of the fractional crystallization.

Enantioselectivities in the homogeneous hydrogenation:

Claims (11)

1. Chromane derivatives, characterized in that they have formula I where R<1> means acyl with 1-6 C atoms, -CO-R5, phenylacetyl, phenoxyacetyl, methoxyacetyl, ethoxyacetyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, 2-iodoethoxycarbonyl, carbobenzoxoxycarbonyl, 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or 4-methoxy-2,3,6-trimethylphenylsulfonyl, R<2> means H or alkyl with 1-6 C atoms, R<3>, R<4> independently means H, alkyl with 1-6 C atoms, CN, Hal or COOR<2>, R means unsubstituted or once or twice with alkyl with 1-6 C atoms , OR or Hal substituted phenyl, X means H, H or O, and Hal means F, Cl, Br or I, as well as their salts, with N-(chroman-2-ylmethyl)-cyclopropanecarboxylic acid amide being excluded. 2. Compounds of formula I according to claim 1, characterized in that they are enantiomers thereof. 3. Compounds of formula I according to claim 1, characterized in that they are: a) N-(4-oxochroman-2-ylmethyl)-acetamide, b) N-(chroman-2-ylmethyl)-acetamide, c) (S)-N-(4-oxochroman-2 -ylmethyl)-acetamide, d) (R)-N-(4-oxochroman-2-ylmethyl)-acetamide, e) (S)-N-(chroman-2-ylmethyl)-acetamide or f) (R)- N-(chroman-2-ylmethyl)-acetamide, as well as their salts. 4. Process for the production of chromane derivatives of formula I according to claim 1, as well as of their salts, where X means O, characterized in that a compound of formula II where R1, R<2>, R<3> and R4 have the meanings specified in claim 1, and X means O, is hydrogenated using an enantiomer-enriching catalyst. 5. Process for the production of chromane derivatives of formula I according to claim 1, as well as of their salts, where X means H,H, characterized in that a compound of formula II where R<1>, R<2>, R<3> and R<4> have the meanings specified in claim 1, and X means O, is hydrogenated using an enantiomer-enriching catalyst and then reduced in the usual way. 6. Process for the production of chromane derivatives of formula I according to claims 4 or 5, characterized in that the enantiomer-enriching catalyst is a transition metal complex. 7. Process for the production of chromane derivatives of formula I according to claims 4, 5 or 6, characterized in that the catalyst is a transition metal complex containing a metal selected from the group consisting of rhodium, iridium, ruthenium and palladium. 8. Process for the production of chromane derivatives of formula I according to claims 4, 5, 6 or 7, characterized in that the catalyst involves a transition metal complex, where the transition metal is complexed with a chiral diphosphane ligand. 9. Use of the compounds of formula I according to claim 1 as intermediates for the synthesis of pharmaceuticals. 10. Use of the compounds of formula I according to claim 1 as intermediates for the synthesis of drugs that have effects on the central nervous system. 11. Process for the production of (R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman and its salts, characterized in that a) a compound of formula II where R<1> has the meaning specified in claim 1, R<2>, R<3> and R<4> mean H, and X means O, is hydrogenated with the help of an enantiomer-enriching catalyst, b) from the thus obtained enantiomer-enriched mixture of the (R) and (S) compounds of formula I, where R<1> has the meaning stated in claim 1, R<2>, R<3> and R<4> mean H, and X means 0, the enantiomeric (R) compound of formula I is recovered, where R<1> has the meaning specified in claim 1, R<2>, R<3> and R<4> mean H, and X means O, by crystallization, c) then reducing in the usual way the enantiomeric (R) compound of formula I, where R<1> has the meaning specified in claim 1, R<2>, R3 and R4 mean H, and X means O, d) from the thus obtained (R) compound of formula I, where R<1> has the meaning stated in claim 1, R<2>, R<3> and R<4> mean H, and X means H,H, the residue R<1> is split off, and e) the thus obtained (R)-(chroman-2-ylmethyl)-amine is converted to its acid addition salt and this is converted in a known manner to (R)-2-[5-(4-fluorophenyl) )-3-pyridylmethylaminomethylj-chroman, and is optionally converted into its acid addition salt, in that the recovery of the (R)-enantiomer by crystallization from the enantiomer-enriched (R,S) mixture can also be carried out after step c) or after step d).